RESEARCH ARTICLE

Preliminary Study of Confounder-Corrected

Fat Fraction and R2* Mapping of Bone
Marrow in Children With Acute Leukemia
Linlin Wang, MD, MSc,1 Dao Wang, MD, PhD,2 Jiao Chen, MD, MSc,2
Mengtian Sun, MD, MSc,1 Dominik Nickel, PhD,3 Stephan Kannengiesser, PhD,3
Feifei Qu, PhD,4 Jingxia Zhu, PhD,4 Cuiping Ren, MD, MSc,1* Yong Zhang, MD, PhD,1* and
Jingliang Cheng, MD, PhD1*

Background: The bone marrow (BM) evaluation of acute leukemia (AL) mainly depends on invasive BM puncture biopsy.
Noninvasive and accurate MR examination technology has potential clinical application value in the BM evaluation of AL
patients. Multi-gradient-echo (MGRE) has been found useful to evaluate changes in BM fat and iron content, but has not
yet been applied in AL.
Purpose: To explore the diagnostic capability of BM infiltration of quantitative BM fat fraction (FF) and R2* values
obtained from a 3D MGRE sequence in children with primary AL.
Study Type: Prospective.
Population/Subjects: Sixty-two pediatric patients with untreated AL and 68 healthy volunteers. AL patients were divided
into acute lymphoblastic leukemia (ALL) (n = 39) and acute myeloid leukemia (AML) (n = 23) groups.
Field Strength/Sequence: 3T, 3D chemical-shift-encoded multi-gradient-echo, T1WI, T2WI, T2_STIR.
Assessment: BM FF and R2* values were assessed by manually drawing regions of interest at the L3, L4, ilium, and 1 cm
below the bilateral trochanter of the femur (upper femur).
Statistical Tests: Independent sample t-tests, variance analysis, Spearman correlation.
Results: BM FF and R2* at L3, L4, ilium, and upper femur, FFtotal and R2*total were significantly lower in the AL than control
group. BM FF did not significantly differ between ALL and AML groups (PL3 = 0.060, PL4 = 0.086, Pilium = 0.179, Pupper
femur = 0.149, and Ptotle = 0.097, respectively). The R2* was significantly lower in ALL group than AML group for L3, L4,
and R2*total. BM FF was moderately positively correlated with R2* in ALL group, and strongly positively correlated in AML
group. Area under the receiver operating characteristic curves showed that BM FF had higher AUC in AL, ALL, and AML
(all AUC = 1.000) than R2* (0.976, 0.996, and 0.941, respectively).
Data Conclusion: MGRE-MRI mapping can be applied to measure BM FF and R2* values, and help evaluate BM infiltration
and iron storage in children with AL.
Evidence Level: 1
Technical Efficacy: 2
J. MAGN. RESON. IMAGING 2023;58:1353–1363.

is increasing yearly.3,4 AL is mainly divided into acute lympho-

A cute leukemia (AL) is among the most common malig-
nant tumors in children and a malignant clonal disease of
the hematopoietic stem cells.1,2 The mortality rate is highest in
blastic leukemia (ALL) and acute myeloid leukemia (AML).
ALL mainly occurs in children and accounts for 80% of all
children with tumor-associated diseases, and the incidence rate leukemias. Currently, leukemia is diagnosed based mainly on

View this article online at wileyonlinelibrary.com. DOI: 10.1002/jmri.28755

Received Jan 5, 2023, Accepted for publication Apr 10, 2023.

*Address reprint requests to: J.C., Zhengzhou, China. E-mail: fccchengjl@zzu.edu.cn, or C.R., Zhengzhou, China. E-mail: fccrencp@zzu.edu.cn, or Y.Z.,
Zhengzhou, China. E-mail: zhy6290@163.com
Linlin Wang and Dao Wang shares co-first authorship.

From the 1MRI Department of the First Affiliated Hospital, Zhengzhou University, Zhengzhou, China; 2Department of Paediatrics of the First Affiliated Hospital,
Zhengzhou University, Zhengzhou, China; 3MR Application Predevelopment, Siemens Healthcare GmbH, Erlangen, Germany; and 4MR Collaboration, Siemens
Healthcare Ltd., Beijing, China

© 2023 International Society for Magnetic Resonance in Medicine. 1353

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Journal of Magnetic Resonance Imaging

bone marrow (BM) biopsies and flow cytometry. Although patients. Sixty-two consecutive patients with untreated ALs
BM biopsies are reliable, they are locally invasive. Therefore, confirmed by BM biopsy in our hospital (35 boys and
repeated examinations increase patients’ physical discomfort 27 girls, mean age 8.56  2.46 years, range 5–15 years) were
and psychological fear of the puncture. Thus, noninvasive and included in the study. The control group comprised 68 age-
accurate auxiliary examination techniques are needed to help matched healthy child volunteers (47 boys and 21 girls, mean
assess the BM condition in children with leukemia to reduce age 8.19  2.60 years, range 5–15 years) (Fig. 3a,b). Refer-
or prevent repeated BM punctures. ring to the 2016 World Health Organization hematopoietic
Fat assessment can show whether the tumoral lesion and lymphoid tumor classification criteria, children with AL
invades the BM and help predict the benign or malignant were divided into the ALL (n = 39, 22 boys and 17 girls,
and extent of BM lesions; moreover, it can prevent >60% of mean age 7.72  2.58 years) (Fig. 3e,f) and AML (n = 23,
biopsies in patients without tumors.5,6 MRI is a noninvasive 13 boys and 10 girls, mean age 9.00  2.47 years) (Fig. 3c,d)
imaging technique that enables assessment of fatty tissue, groups.20 The AML group included types M0 (n = 1), M2
especially in the liver rapid developments in dual-echo (n = 11), M3 (n = 8), M4 (n = 2), and M5 (n = 1).
Dixon-type water-fat separation and multi-echo methods have
enabled MR-based assessment of fat to become widely used
in clinical practice.7–9 Early applications to BM quantification
used the three-echo approach to correct the T2* effect.10
State-of-the-art implementations are typically based on 3D
chemical-shift-encoded multi-gradient-echo (MGRE) acquisi-
tions with simultaneous data fitting for “proton density fat
fraction” (PDFF) and transverse relaxation rate (R2*) while
accounting for confounding effects like T1 relaxation and the
spectral complexity of fat.11 Compared with the reference
standard multi-echo single-voxel MR spectroscopy (MRS),
studies have confirmed that the fat content obtained by
MGRE MRI shows better correlation and consistency.12–14
Previous research has also reported the accuracy of R2* mea-
surements (or its inverse, T2*) for the iron content in
abdominal organs and models experiment.15–17 MGRE MRI
allows obtaining quantitative BM fat fraction (FF) and R2*
values with noninvasive imaging.
AL mainly invades the BM and affects the hematopoi-
etic system, especially the red BM, which can cause the fat
content in the BM to decrease.18 In the pathological state,
the yellow BM may revert to red BM, whose content will
then also decrease. Additionally, the iron content in the BM
will change with the course and blood transfusion treatment
that would affect the prognosis.19 The use of R2* values to
determine the BM iron content in patients with primary AL
is not commonly reported in the literature, and BM FF is
rarely reported in pediatric patients with primary AL.
Therefore, the goal of this study was to quantitatively
measure BM FF and R2* values in the lower lumbar verte-
brae, pelvis and upper femur of children with MGRE; to
investigate myelogram, hemogram, FF and R2* correlations FIGURE 3: (a and b) Male, 12 years, FF and R2* picture of a
and to evaluate the diagnostic ability for BM infiltration of control, comparison with muscle tissue, both FF and R2*
pictures show high signals in bone marrow; the former has
this technique for AL.
higher signal. (c and d) Female, 12 years, FF and R2* picture of
AML patient, FF shows that the bone marrow signal is diffusely
reduced and equal to the muscle tissue signal, R2* picture
Patients and Methods shows bone marrow signal is close to muscle tissue. (e and f)
Female, 7 years, ALL patient, on FF and R2* map, bone marrow
Participants
signal performance is consistent with AML patients (the oval
The institutional review board of our hospital approved the represents the area of interest, at the L3, L4, ilium, and upper
study and written informed consent was obtained from all femur levels).

1354 Volume 58, No. 5


Wang et al.: Preliminary Study of Confounder-Corrected Fat Fraction
Myelograms were observed for the percentages of primitive
and immature cells. Inclusion criteria for the control subjects
were no abnormalities in the peripheral blood; no blood or
BM system disease. Four patients were excluded because of
inadequate examination results or motion artifacts.
MRI Protocol
An MRI scan was performed on all participants using a 3T
system (MAGNETOM Prisma, Siemens Healthcare,
Erlangen, Germany) with one (for patients 5–12 years) or
two (for patients 13–15 years) 18-channel phased-array body
coils in combination with a 32-channel phased-array spine
coil. MRI examinations were performed within 48 hours of
the BM biopsies. All participants were examined in supine
position, with both feet together. The coil covered the lower
lumbar vertebrae, pelvis, and upper femur.
The MRI protocol consisted on: the multi-gradient-
echo prototype sequence (MGRE), T1-weighted imaging
(T1WI), T2-weighted imaging (T2WI) and T2-weighted
short-TI inversion recovery (T2_STIR) sequences. Table 1
lists all MRI sequence parameters. MGRE used coronal slice
orientation, a lower parallel imaging acceleration factor, mul-
tiple signal averages, no breath-holding, and low-rank den-
oising of the source images.21 This prototype sequence can
collect high spatial resolution images that generates FF with
comparable accuracy of spectroscopy. Quantitative FF and
R2* maps were automatically generated inline after data
acquisition from the MGRE data by a confounder-corrected
multi-step fitting approach.22
Quantitative Image Assessment
After scanning, the MGRE was automatically reconstructed
to generate the FF map and R2* relaxation maps, and all
images were transferred to a processing workstation (syngo.
via, Siemens Healthcare, Erlangen, Germany) for analysis. A
radiologist (L.W.) involved in the MRI diagnosis for 12 years
TABLE 1. MRI scan parameters
Resolution (mm3) TR (msec) TE (msec) Averages
MGRE 1.1  1.1  3.5 9.15 1.07, 2.24,
3.41, 4.58,
5.75, 6.92
T1WI 0.8  0.8  5.0 550 21
T2WI 0.8  0.8  4.0 4000 86
T2_STIR 1.4  1.4  4.0 6000 46
MGRE = multi-gradient-echo; TR = repetition time; TE = echo time; TIWI = T1-weighted imaging; T2WI = T2-weighted imaging;
T2_STIR = T2-weighted short-TI inversion recovery; GRAPPA = Generalized Autocalibrating Partially Parallel Acquisitions.
November 2023
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manually delineated regions of interest (ROI). The ROIs
were manually drawn on the FF maps (Fig. 3a,c,e). At the
same time, the ROIs were copied to the R2* relaxation maps
(Fig. 3b,d,f). The ROIs in the medullary cavity areas of the
median levels of the L3 and L4 vertebrae, the bilateral ilium,
and the bilateral 1 cm under the bilateral lesser trochanter of
the upper femur were drawn in turn and using conventional
coronal T1WI, T2WI, and T2_STIR sequences as references.
Quantitative BM FF and R2* values were obtained as mean
values over the ROIs from the MGRE FF and R2* map,
respectively. The ROIs were avoided the bone cortex and ter-
minal plate of the vertebral body as much as possible. Care
was taken to ensure that the size and position of the ROIs
were as same or similar as possible because the ROI may vary
slightly owing to the influence of the position of the medul-
lary cavity. Each ROI was measured three times, and the
average was taken as the final result for any site. In this arti-
cle, FF and R2* values of ilium and 1 cm under the bilateral
lesser trochanter of the upper femur were the average value
measured from the bilateral sites. Finally, results of the indi-
vidual regions of interest were averaged together and reported
as FFtotal and R2*total.
Statistical Analysis
SPSS 21.0 software (IBM Corp, Armonk, NY, USA) was
used for statistical analyses. Continuous values were expressed
as mean  standard deviation. Independent sample t-tests
were used to compare the BM FF and R2* values,
myelogram, lymphocyte percentage, and neutrophil percent-
age between groups. The FF and R2* values between posi-
tions were compared by variance analysis. Pearson correlation
analysis was performed for the BM FF, R2* value, and labo-
ratory indicators that were normally distributed. Spearman
correlation analysis was used for non-normal distributions.
Receiver operating characteristic (ROC) curves were used to
analyze the diagnostic capability of the BM FF and R2*
GRAPPA
Factor Flip Angle ( ) Orientation Scan Time
8 2 4 Coronal 2 minutes 18 s
1 3 140 Coronal 1 minute 12 s
1 2 150 Coronal 1 minute 22 s
1 2 150 Coronal 1 minute 20 s
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Journal of Magnetic Resonance Imaging

values, which was performed with the mean BM FF and R2*
values obtained from bilateral iliac bones of AL, ALL, and
AML patients at common puncture sites. The ROC AUC
was assessed with a confidence interval (IC) of 95%. P < 0.05
was considered statistically significant.
Results
Comparison of BM FF and R2* Values Between the
AL and Control Groups
Age did not significantly differ between the AL and control
groups (P = 0.412). The BM FF and R2* values at the L3,
L4, ilium, upper femur, as well as FFtotal and R2*total levels,
were significantly lower in the AL group than in the controls
(Table 2).
The BM FF in the control group gradually increased
from the L3, L4, and ilium to the upper femur levels, and
R2* values also showed a gradually increased from the L3, L4
to ilium except for upper femur levels. However, the BM FF
and R2* values between L3 and L4 did not significantly dif-
fer (P = 0.246 and P = 0.589, respectively). Significant dif-
ferences were found between the L3 and ilium, L3 and upper
femur, L4 and ilium, L4 and upper femur, and ilium and
upper femur. R2* values were significantly lower in the upper
femur than in the L3, L4, and ilium.
In the AL group, the FF was lower for the L3 and L4
vertebrae than for the ilium and upper femur, but not signifi-
cantly (P = 0.083). The R2* values were significantly lower
in the upper femur than at the L3, L4, and ilium levels
(Table 2).
Comparison of BM FF and R2* Values Between the
ALL and AML Groups
Age did not significantly differ between the ALL (n = 39)
and AML (n = 23) groups (P = 0.060). Both groups showed
inconsistent BM FF and R2* values in whether there is a sta-
tistical difference. These values for the L3, L4, ilium, upper
femur, as well as FFtotal and R2*total were lower in the ALL
group than in the AML group, but BM FF did not signifi-
cantly differ (PL3 = 0.060, PL4 = 0.086, Pilium = 0.179,
Pupper femur = 0.149, and Ptotle = 0.097, respectively). The
R2* value was significantly lower in the ALL group than in
the AML group for L3, L4, and R2*total. R2* values in the
ilium and upper femur were slightly lower in the ALL group
than in the AML group, but not significantly (P = 0.052 and
P = 0.646, respectively) (Table 3).
BM FF did not differ significantly for the L3, L4, ilium
and femur in the ALL group (P = 0.066). In the AML
group, the L3 and L4 BM FFs were lower than those of
the ilium and femur, but not significantly (P = 0.568).
However, the R2* values of the upper femur in both
groups were significantly lower than those of the L3, L4,
and ilium. No significant difference was found between
L3 and L4 (PALL = 0.900; PAML = 0.926), L3 and the
ilium (PALL = 0.329; PAML = 0.902), and L4 and the
ilium (PALL = 0.394; PAML = 0.976) (Table 3).
Correlation Analysis of BM FF and R2* Value in the
Control, AL, ALL, and AML Groups
Correlation analysis was performed on the mean values of the
FF and R2* values in the control group and patients, and the

TABLE 2. Clinical data and imaging characteristics of the control and AL groups

(FF [%]) (R2* [s 1])

Variable Control AL Group P Value Control AL Group P Value
Participants n = 68 n = 62 n = 68 n = 62
Sex (M/F) 47/21 35/27 47/21 35/27
Age (years) 8.56  2.46 8.19  2.60 0.412 8.56  2.46 8.19  2.60 0.412
Target location
L3 40.19  9.43 2.71  2.93 <0.05 147.62  25.21 87.37  30.27 <0.05
L4 41.85  9.76 2.99  3.28 <0.05 149.73  23.84 87.45  26.52 <0.05
Ilium 54.19  5.50a 3.92  4.65 <0.05 164.23  18.36b 90.19  26.77 <0.05
Femur 62.37  8.01 a
4.38  5.18 <0.05 96.73  23.23 b
57.32  28.92 c
<0.05
Total 49.65  6.68 3.50  3.55 <0.05 139.58  15.84 80.58  23.53 <0.05

M = Male; F = Female; FF = fat fraction; R2* = R2* values; AL = acute leukemia.

a
Significant differences in bone marrow FF between L3 and ilium, L3 and femur, L4 and ilium, L4 and femur, ilium and femur.
b
Significant differences in R2* values between L3 and ilium, L3 and femur, L4 and ilium, L4 and femur, ilium and femur.
c
Significant differences in R2* values between L3 and femur, L4 and femur, and ilium and femur.

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Wang et al.: Preliminary Study of Confounder-Corrected Fat Fraction

TABLE 3. Clinical data and imaging characteristics of ALL and AML patients

Result (FF [%]) Result (R2*[s 1])

Variable ALL AML P Value ALL AML P Value
Participants 39 23 39 23
Sex (M/F) 22/17 13/10 22/17 13/10
Age (years) 7.72  2.58 9.00  2.47 0.060 7.72  2.58 9.00  2.47 0.060
Target location
L3 2.10  1.39 3.75  4.33 0.060 79.30  22.84 101.06  36.43 0.015
L4 2.37  2.22 4.03  4.41 0.086 79.96  18.01 100.16  33.48 0.012
Ilium 3.18  2.75 5.19  6.65 0.179 84.49  20.85 99.87  32.87 0.052
Femur 3.54  3.85 5.81  6.73 0.149 56.01  30.16a 59.54  27.19a 0.646
Total 2.79  1.99 4.69  5.07 0.097 74.94  17.79 90.16  28.92 0.029

M = Male; F = Female; ALL = acute lymphoblastic leukemia; AML = acute myeloid leukemia; FF = fat fraction; R2* = R2* values.
a
Significant differences in R2* values between L3 and femur, L4 and femur, and ilium and femur.

mean values of BM FF and R2* values are derived from the TABLE 4. Spearman correlations between AL patient
sum of L3, L4, ilium, and upper femur, respectively. No cor- bone marrow FF and R2* values
relation was found between BM FF and R2* values in the
control group (R = 0.134, P = 0.277). BM FF was moder- Parameters n R P Value
ately positively correlated with R2* values in all patients FFcon and R2*con 68 0.134 0.277
(R = 0.499), and in the ALL group (R = 0.476). FF and FFAL and R2*AL 62 0.499 0.000*
R2* values were strongly positively correlated in the AML
group (R = 0.615; Table 4; Fig. 1a–d). FFALL and R2*ALL 39 0.472 0.002*
FFAML and R2*AML 23 0.615 0.002*

AL = acute leukemia; ALL = acute lymphoblastic leukemia;

Comparison of Laboratory Indicators and
Correlation Analysis Between the ALL and AML
Groups
The proportions of primitive and naive leukemia cells on the
myelogram and the percentage of peripheral blood lympho-
cytes were significantly higher in the ALL group than in the
AML group. The percentage of peripheral blood neutrophils
was significantly lower in the ALL group than in the AML
group (Table 5).
No significant correlation was found between the BM
FF and R2* values and the myelogram and percentage of
peripheral blood lymphocytes and neutrophils in the ALL
group (P = 0.271, 0.925, 0.864, 0.469, 0.357, and 0.175,
respectively). In the AML group, BM FF was moderately neg-
atively correlated with myelogram and neutrophil percentage
(R = 0.595 and R = 0.420, respectively) and significantly
positively correlated with lymphocyte percentage
(R = 0.676). The AML R2* value was moderately positively
correlated with the lymphocyte percentage (R = 0.517), and
no significant correlation was found between the myelogram
and neutrophil percentage (R = 0.346 and R = 0.388,
AML = acute myeloid leukemia; FFcon = fat fraction of control
groups; R2*con = R2* value of control groups; FFAL = fat frac-
tion of AL; R2*AL = R2* value of AL; FFALL = fat fraction of
ALL; FFAML = fat fraction of AML; R2*ALL = R2* value of
ALL; R2*AML = R2* value of AML.
respectively; P = 0.106 and P = 0.067, respectively;
Table 6).
Diagnostic Performance Comparison of BM FF and
R2*Values in AL, ALL, and AML Patients
BM FF and R2* values had high diagnostic performance for all
patients, with BM FF performing the best (Table 7; Fig. 2a–c).
The area under the curve (AUC) of the AL (1.000;
95% confidence interval [95% CI]: 0.972–1.000) was slightly
higher than that of the ALL (1.000; 95% CI: 0.966–1.000)
and AML (1.000; 95% CI: 0.960–1.000) BM FFs. The 95%
CIs of the R2* values were 0.932–0.995, 0.959–1.000, and
0.871–0.980 for AL, ALL, and AML, respectively. The sensi-
tivity of the BM FF for all patients was 100%, which was

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Journal of Magnetic Resonance Imaging

FIGURE 1: Correlation analysis of the BM FF and R2* values in the control (a), AL (b), ALL (c), and AML (d) groups and of the mean of
the sum of the FF and R2 values. AL = acute leukemia; ALL = acute lymphoblastic leukemia; AML = acute myeloid leukemia.

TABLE 5. Comparison of laboratory indicators between ALL and AML groups

Myelogram (%) Lymphocyte percentage (%) Neutrophil percentage (%)

Parameters n Mean  SD p Value Mean  SD P Value Mean  SD P Value
ALL 39 88.14  16.29 0.002 76.05  12.85 <0.05 16.19  11.41 <0.05
AML 23 71.19  22.47 40.74  24.33 40.39  25.49

ALL = acute lymphoblastic leukemia; AML = acute myeloid leukemia.

higher than that of the corresponding BM R2* value (88.71, Discussion

94.87, and 78.26, respectively). The specificity of both
parameters was the same (100%). The maximum reference
values of the BM FF in the AL, ALL, and AML patients were
22.38%, 12.81%, and 22.38%, respectively, and the maxi-
mum reference values of the R2* values were 126.41, 111.7,
and 126.41 s 1, respectively (Table 7; Fig. 2a–c).
In this study, we investigated the potential diagnostic ability
of MGRE in diffuse BM infiltration of AL in children. We
found that quantitative BM FF and R2* values can accurately
evaluate the changes in fat content and the iron content in
the BM of AL. Compared with normal children, quantitative
BM FF significantly decreased in the BM of children with

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Wang et al.: Preliminary Study of Confounder-Corrected Fat Fraction
TABLE 6. Spearman correlations between laboratory indicators and FF and R2* values of AL patients
Correlation
Variable R P Value
FFALL and M 0.181 0.271
FFALL and LP 0.010 0.952
FFALL and NP 0.028 0.864
R2*ALL and M 0.120 0.469
R2 ALL and LP 0.152 0.357
R2*ALL and NP 0.222 0.175
AL = acute leukemia; ALL = acute lymphoblastic leukemia; AML = acute myeloid leukemia; FFALL = fat fraction of ALL;
FFAML = fat fraction of AML; R2*ALL = R2* value of ALL; R2*AML = R2*value of AML; M = myelogram; LP = lymphocyte per-
centage; NP = neutrophil percentage.
AL, especially in ALL patients. The BM R2* value was signif-
icantly correlated with BM FF. In addition, we also found
that ALL and AML showed significant differences in
Myelogram, lymphocyte percentage (LP), and neutrophil per-
centage (NP). In contrast, the BM FF of AML patients
showed a moderate or obvious correlation with Myelogram,
LP, and NP. The R2* value showed a moderate correlation
with LP, which differed from ALL. Combined with the AUC
of ROC, BM FF, and R2* values have high diagnostic per-
formance for patients with AL, ALL, and AML. These results
may be helpful for the quantitative evaluation of diffuse BM
infiltration in AL patients with quantitative FF and R2*
values.
Human BM is divided into hematopoietic red BM and
fatty yellow BM. The compositions of red and yellow BM
differ as follows: red marrow contains 40% water, 40% fat,
and 20% protein; yellow marrow contains 15% water, 80%
fat, and 5% protein.23 The distribution of red and yellow
BM changes dynamically; adipose tissue gradually replaces the
hematopoietic tissue in long bones from shortly after birth to
childhood, becoming yellow BM and reaching the state of
adult BM at 25 years of age.24 Consequently, children’s BM
undergoes rapid age-related changes, and the fat content in
the BM and the FF are lower than those in adults. To avoid
the influence of age in this study, the control group com-
prised age-matched, healthy children. Consequently, it is
important that in this study, age did not significantly differ
between the patients and controls.
BM infiltration in leukemia first occurs in the red BM,
which is related to the origin of leukemic cells in the red BM
and the abundant blood supply.18 Therefore, in this study,
the vertebral body, ilium, and upper femur with rich red BM
were selected as the target sites. The FFs in children with AL
at the L3, L4, bilateral ilium and 1 cm under the bilateral
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Correlation
Variable R P Value
FFAML and M 0.595 0.003*
FFAML and LP 0.676 0.000*
FFAML and NP 0.420 0.046*
R2*AML and M 0.346 0.106
R2*AML and LP 0.517 0.011*
R2*AML and NP 0.388 0.067
lesser trochanter were significantly lower than those in healthy
children at the same age, but no significant difference was
found between ALL and AML groups at L3, L4, bilateral
ilium and 1 cm under the bilateral lesser trochanter. Normal
tissue is replaced by tumor cells because of the abnormal pro-
liferation of primitive and immature cells in BM hematopoi-
etic tissue.25 When leukemia cells infiltrate BM, the yellow
BM reverts to red BM in the pathological state, and when
normal BM is replaced or reversed, the proportion of water
and fat in BM changes.26 Different degrees of leukemia cells
were distributed in the vertebral body, pelvis, and upper
femur with rich red BM, and a decreased fat content in the
BM resulted in a significant decrease in the BM FF. The
decrease of fat content in BM is shown by obvious signal
reduction in FF map (Fig. 3c,e), and the BM signal of normal
children is relatively high (Fig. 3a). Nguyen et al reported
that the decrease in leukemia cells is related to an increase in
the area of BM fat.27 Compared with the control group, the
areas of BM occupied by adipocytes were significantly
reduced in patients with ALL. Our results are consistent with
those of Nguyen et al in that the BM FFs of the L3, L4,
ilium, and upper femur in AL patients were generally
reduced. The R2* values were significantly lower in the AL
group than in the controls. In AL, the decreased iron content
in the BM may be caused by the special iron intake mecha-
nism to obtain iron from the host to meet the abnormal pro-
liferation needs of leukemia cells. Regarding the significance
of BM iron content in patients with AL, research suggests
that reduced BM iron storage can increase the response of
patients with ALL.19 Iron overload (grade ≥3) will increase
patients’ tolerance to treatment and BM recurrence risk.19
Further studies of the BM iron reduction mechanism in
patients with AL should provide new treatment options and
methods of prognosis evaluation for patients with leukemia.
1359
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Journal of Magnetic Resonance Imaging

The BM distributions also differed in the control group.

AL = patients with acute leukemia; ALL = patients with acute lymphoblastic leukemia; AML = patients with acute myeloid leukemia; FF = bone marrow fat fraction of iliac bone;
0.941 (0.871–0.980)
Healthy children showed higher FFs in the upper femur,

78.26 (56.3–92.5)
100 (94.7–100)
followed by the ilium, and finally the L3 and L4. FFs did not

1
≤126.41 s
<0.001
significantly differ between the L3 and L4 vertebrae; however,

0.783
R2*
significant differences were found between the L3 and ilium,

R2* = bone marrow R2* value of iliac bone; sensitivity and specificity rows are 95% confidence intervals. AUC = area under the ROC curve; MCV = maximum reference value.
L3 and upper femur, L4 and ilium, L4 and upper femur, and
ilium and upper femur. This distribution is consistent with
AML

the normal growth patterns of children because BM transfor-

mation occurs earlier and faster in children’s long bones than
1.000 (0.960–1.000) in the central axis and pelvis, although the pelvic bone also
100 (85.2–100)
100 (94.7–100)

undergoes transformation, but it is slower than that of the

≤22.38%
<0.001
1.00
femur and occurs earlier than that of the vertebrae.23 There-
FF

fore, the fat content is more abundant in the long bones than
in the central axis and pelvis, and the FF is higher in the
upper femur, followed by the pelvis, L3, and L4 vertebrae.
The R2* value of the control group increased gradually at the
0.996 (0.959–1.000)

L3, L4, and ilium, which was consistent with the perfor-
94.87 (82.7–99.4)
100 (94.7–100)

mance of the BM FF, but the level of the upper femur

1

<0.001
≤111.7 s

decreased, which was inconsistent with the BM FF perfor-

0.949
R2*

mance. The reasons for this require further investigation. The

increasing and decreasing trend of the R2* values from the
TABLE 7. Diagnostic performance of iliac bone marrow FF and R2*value for AL, ALL, AML patients

L3, L4, ilium and upper femur were consistent with the FF
ALL

in the AL group. The change in the R2* value was accompa-

nied by a change in the BM FF, which is consistent with the
1.000 (0.966–1.000)

results of the liver study by Bashir et al.28 It has to be noted

100 (91.0–100)
100 (94.7–100)

that the signal model for the (simultaneous) parameter fitting

≤12.81%
<0.001
1.00
FF

of FF and R2* used in this study was primarily designed for

quantifying liver fat, so it is possible that some correlation
between the two parameters is caused by inexact modeling of
the potentially different signal evolution of BM compared
with liver parenchyma. However, the magnitude of change in
0.976 (0.932–0.995)

FF and R2* makes it likely that the observed correlation has

88.71 (78.1–95.3)
100 (94.7–100)

a primarily physiological reason.

≤126.41 s
<0.001
0.887

Comparisons of the BM FF and R2* values between ALL

R2*

and AML groups showed that the R2* values changed as the
BM FF changed. The FF and R2* values in the ALL group
were generally lower than those in the AML group at the L3,
L4, ilium, upper femur, and overall levels, which may be related
AL

to the different proportions of primary and immature cells in

1.000 (0.972–1.000)
100 (94.2–100)
100 (94.7–100)

the BM of patients with ALL and AML. The proportion of

≤22.38%

abnormal proliferation of primary and immature leukemia cells

<0.001
1.00
FF

was higher in the ALL group than in the AML group; thus, the
BM FF in the ALL group was generally lower than that in the
AML group, which is consistent with the pathological manifesta-
tions of leukemia in the BM. However, no significant differences
were found in the FFs between the groups. The R2* value of
Sensitivity (95% CI)
Specificity (95% CI)

the ALL group was significantly lower than that of the AML
group at the L3, L4, and total levels. This was consistent with
AUC (95% CI)
Youden index J

the BM FF but appears to be more sensitive than the FF

response. However, no significant differences were found
Variable

P value

between the two groups at the ilium and upper femur levels,
MCV

but the R2* values were lower at the upper femur levels than at
the L3, L4 levels and ilium for the ALL and AML groups.

1360 Volume 58, No. 5


Wang et al.: Preliminary Study of Confounder-Corrected Fat Fraction
FIGURE 2: ROC curve analysis of BM FF and R2* values in AL, ALL, and AML patients. (a) ROC curves of FF and R2* value of AL
patients. (b) ROC curves of FF and R2*value of ALL patients. (c) ROC curves of FF and R2* value of AML patients. Diagonal line
denotes reference. AL = acute leukemia; ALL = acute lymphoblastic leukemia; AML = acute myeloid leukemia; FF = fat fraction;
BM = bone marrow; ROC = Receiver operating characteristic.
Comparing the different levels in the ALL and AML
groups showed no significant differences in BM FFs between
groups at any level. The differences in BM FF between levels
was less obvious in the ALL group than in the AML group.
Specifically, in the AML group, the FFs of the L3 and L4 ver-
tebrae were lower than those of the ilium and upper femur,
but these levels did not significantly differ in the ALL group.
Therefore, compared with AML, we believe that ALL has
higher invasion and spread characteristics, and the area of
BM fat decreases more significantly and is more obvious in
the ilium and upper femur. This may be related to the pro-
portion of primitive and immature cells, biological character-
istics, and different chemical compositions of the cells.18 The
changes in R2* values between levels were also generally con-
sistent with the BM FFs. The R2* values were generally lower
in the ALL group than in the AML group, and in the ALL
and AML groups, the R2* values were significantly lower in
the upper femur than in the L3, L4, and ilium. The reasons
for the lower R2* values in the upper femur are unclear and
require further study. Due to anemia, leukemia patients often
need blood transfusion treatment. Frequent or massive blood
transfusion treatment can cause systemic iron overload. Some
published works reported that excessive iron can damage hema-
topoiesis by inducing apoptosis and cell cycle arrest, leading to
a decline in the ratio and clonogenic function of hematopoietic
stem and progenitor stem cells.29,30 Brissot et al mentioned in
the study that excessive iron in leukemia patients has harmful
effects on both hematopoietic function and prognosis, espe-
cially after hematopoietic stem cell transplantation.31 Moafi
et al reported that the increase of BM iron storage (BMIS) at
the end of the first year of treatment was related to the inci-
dence of drug resistance and the risk of relapse.19 Therefore,
MGRE could also be a useful tool to monitor the variation of
iron content in BM during the treatment of leukemia.
Correlation analysis showed that the BM FF and R2*
values were correlated to varying degrees and were moderately
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positively correlated in patients with AL, ALL. The R2* value
decreased as the BM FF decreased, which was consistent with
the results of Bashir et al.28 Compared with the AL and ALL
groups, the correlation was higher between the BM FF and
R2* values in the AML group.
Myelogram analysis showed that the proportion of pri-
mary and immature leukemia cells was significantly higher in
the ALL group than in the AML group, which explains why
the BM FF at each site was lower in the ALL group than in
the AML group. The BM FF in the AML group was moder-
ately negatively correlated with the myelogram, but the R2*
value was not, indicating that the BM FF in the AML group
decreased as the numbers of primitive and immature cells
increased. No significant correlation was found between the
myelogram and FF or myelogram and R2* value in the ALL
group.
There is a significant difference between ALL and AML
groups in the lymphocyte percentage and neutrophil percent-
age in peripheral blood, which may be different from differ-
ent subtypes of leukemia in the type, differentiation, chemical
composition, and proliferation rate of tumor cells. ALL origi-
nates from B-line or T-line cells of lymphocytes and prolifer-
ates abnormally in BM. AML is a malignant myeloid
hematopoietic stem/progenitor cells disease, characterized by
abnormal proliferation of primitive and juvenile myeloid cells
in BM and peripheral blood. In the AML group, the labora-
tory study showed that the BM FF and R2* values were sig-
nificantly correlated with the percentage of lymphocytes, and
the BM FF was significantly negatively correlated with the
percentage of neutrophils, which can provide additional infor-
mation related to the BM fat content and iron storage.
The results of this study suggest that the obtained FF
and R2* values, especially the FF, are the best parameters for
distinguishing between normal hematopoietic BM and BM
infiltration in leukemia, consistent with previously reported
results.32 The literature reports that the FF has good
1361

Journal of Magnetic Resonance Imaging
diagnostic performance for differentiating benign and malig-
nant BM lesions such as spinal Schumacher’s nodules from
metastatic tumors.33 Schmeel et al also confirmed that PDFF
has high diagnostic accuracy, sensitivity, and specificity in dif-
ferentiating benign and malignant BM lesions through ROC
curve analysis.34 Disler et al reported that chemical
shiftencoded MRI can help predict the likelihood of neoplas-
tic or nonneoplastic lesions with high diagnostic perfor-
mance.35 Similarly, R2* value can accurately evaluate the
iron content in BM. Clinically, the evaluation of the iron
content in patients with AL is usually performed on the labo-
ratory index serum ferritin, which is considered the most
commonly used parameter.36 However, serum ferritin is also
an indicator of inflammation and acute phase reaction, and
has a poor correlation with the actual iron content in the
body.36,37 Therefore, inflammatory infection, tumors and
autoimmune disease can affect the measured value of serum
ferritin. Relevant researchers reported that MRI can achieve
high sensitivity and specificity in the analysis of liver iron
content, and it is considered the best surrogate marker of
total body iron content.38,39
Limitations
The first one is the sample size of the study is small. The
smaller sample size may cause some issues. First, the lower
parameter values obtained in some patients may have
affected the results of the correlation analysis. Second, many
factors can cause changes in BM FF and R2* values in ALL
patients, and the increased proportion of primitive and
immature cells in the BM is only one factor. At the last, the
results suggest that local pathological samples from BM
biopsies may not represent the overall situation of the BM
changes in these patients. Therefore, whether the
myelogram and BM FF and R2* values are correlated in
ALL requires further research with a larger sample. The sec-
ond one is that the age range of the patient cohort is quite
large. Future studies should comprise subgroups with differ-
ent age ranges so that FF and R2* may be more sensitive
and accurate in the diagnosis of AL, ALL and AML in those
subgroups. The third limitation is that the lack of compari-
son of BM changes before and after treatment, and a lack of
prognosis evaluation. Future studies should include follow-
up of the patients’ BM changes to assist in clinical pre-
treatment evaluations, monitoring of treatment effects, and
prognostic evaluations.
Conclusion
MGRE MRI is a noninvasive technique to evaluate FF and
R2* value in BM of AL patients. It could be a powerful tool
to evaluate BM abnormalities in children with AL.
1362
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Acknowledgments
This study was supported by a public service platform for
artificial intelligence screening and auxiliary diagnosis for the
medical and health industry, Ministry of Industry and Infor-
mation Technology of the People’s Republic of China
(2020-0103-3-1).
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